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Originally published as JCO Early Release 10.1200/JCO.2008.20.3034 on December 8 2008 © 2009 American Society of Clinical Oncology.
Activity of Sunitinib in Patients With Advanced Neuroendocrine Tumors
Medical Oncology Unit 2, Fondazione Istituto de Ricovero e Cura a Carattere Scientifico Istituto Nazionale dei Tumori, Milano, Italy To the Editor: Following a careful reading of the Kulke et al's1 "Activity of Sunitinib in Patients With Advanced Neuroendocrine Tumors" in Journal of Clinical Oncology, dealing with the antitumor efficacy of sunitinib in the treatment of neuroendocrine tumors, we would like to make some remarks and clarifications. It is common knowledge that neuroendocrine carcinomas represent a rather heterogeneous group of neoplasms characterized by an extremely variable and unpredictable course, and it is well known, for instance, that carcinoids of the gastrointestinal tract are marked out by a natural history particularly indolent even in situations of advanced nonresectable disease. Some prognostic factors such as cell differentiation and cell proliferation index, sites and number of metastases, presence of a tumor-related syndrome, and overexpression of receptors for somatostatin analogs have been largely identified and documented and significantly correlate with the clinical evolution of the disease.2 Conversely, the antitumor activity of different chemotherapeutic agents in other types of carcinoids originating from different body areas is definitely unsatisfactory in terms of objective responses. Therefore, taking into account the adverse effects of the chemotherapeutic agents utilized; their limited impact on tumor growth; and the indolent course of the carcinoid, chiefly in its typical form originating from ileum, currently in most cases the standard treatment is simply based on the observation or on the use of somatostatin analogs with symptomatic purposes.3 Neuroendocrine carcinomas originating from pancreas usually biologically behave in a more aggressive way, even though extremely variable. Often histologic types characterized by a low proliferation index and by a high cell differentiation degree show a natural indolent history comparable to that of carcinoids originating in the small bowel. Particularly due to the rarity of prospective randomized clinical studies so far carried out, even though the antitumor efficacy of some chemotherapeutic regimens containing cisplatin or streptozotocin undoubtedly turned out superior in terms of objective tumor regression, the evaluation of patients in terms of survival has remained hardly and questionably quantifiable.4,5 Besides, it cannot be underestimated the toxicity profile of such therapies since it clearly appears that the treatment of the metastatic disease, whose major aim is to guarantee the improvement of quality of life, primarily requires to be well tolerated. Sunitinib is an important multikinase inhibitor whose activity has been definitely proven in several solid neoplasms. In patients with advanced renal cell tumors in particular, a benefit in terms of objective responses and progression-free survival in both untreated and previously treated patients has been clearly demonstrated. Consequently, sunitinib has been acknowledged as the reference standard treatment for primary metastatic renal tumors at low-intermediate risk according to the Memorial Sloan-Kettering Cancer Center risk classification criteria.6,7 This therapy, however, is rather often associated with a significant incidence of adverse effects that frequently calls for dosage adjustments; and since the optimal duration of treatment has not yet well established, the administration of this drug is continued until disease progression. The main biologic rationale of the study by Kulke et al1 lies in the presence of elevated values of vascular endothelial growth factor and of its receptor in neuroendocrine tumors. In this regard, we deem appropriate to remind that results definitely encouraging have been achieved in other phase II studies evaluating other targeted therapies such as bevacizumab, sorafenib, and everolimus in neuroendocrine tumors. However, neuroendocrine tumors completely differ from renal carcinoma and, therefore, several controversies remain open. It should be interesting to have additional information concerning the cell proliferation index and the degree of cell differentiation of the pancreatic histotypes treated. It stands to reason that the evidence of objective responses and 62% tumor shrinkage should take more significance in case of a disease with a relatively indolent course. Moreover, due to the scarcity of the case list and to the heterogeneity of cases, it should be difficult in any case to give significance to progression-free survival. It is our conviction that when we are dealing with a biologically indolent disease, a therapeutic option particularly aiming at the preservation of patient's quality of life should be taken into serious consideration. In neuroendocrine tumors, continuous administration of sunitinib until disease progression could imply a long-lasting treatment (even years) exposing the patient to the risk of onset of late toxicities without, at least for the time being, a clear evidence of prolongation of survival. In addition, there should be a significant rise of costs of therapy and of the management of adverse effects. In conclusion, there is no doubt about the value of this study which proves and stresses the role of targeted therapies, particularly sunitinib, in the treatment of neuroendocrine tumors. However, we firmly believe it is extremely important to optimize the use of this agent limiting its effect to more aggressive and nonindolent neuroendocrine tumors or for cytoreduction purposes before surgery. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. NOTES published online ahead of print at www.jco.org on December 8, 2008 REFERENCES
1. Kulke MH, Lenz H-J, Meropol NJ, et al: Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol 26:3403-3410, 2008 2. Yao J, Hassan M, Phan A, et al: One hundred years after "carcinoid": Epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 26:3063-3072, 2008 3. Bajetta E, Procopio G, Ferrari L, et al: Update on the treatment of neuroendocrine tumors. Expert Rev Anticancer Ther 3:631-642, 2003[CrossRef][Medline] 4. Moertel CG, Kvols LK, O'Connell MJ, et al: Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin: Evidence of major therapeutic activity in the anaplastic variants of these neoplasms. Cancer 68:227-232, 1991[CrossRef][Medline] 5. Moertel CG, Lefkopoulo M, Lipsitz S, et al: Streptozocin-doxorubicin, streptozocin-fluorouracil, or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med 326:519-523, 1992[Abstract] 6. Motzer RJ, Rini BI, Bukowski RM, et al: Sunitinib in patients with metastatic renal cell carcinoma. JAMA 295:2516-2524, 2006 7. Motzer RJ, Hutson TE, Tomczak P, et al: Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356:115-124, 2007
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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